Treatment of HIV-Associated Cognitive Impairment

HIV 相关认知障碍的治疗

• 批准号: 8233952
• 负责人: Ana-Claire Lew Meyer
• 金额: $ 13.55万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-19 至 2016-07-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8233952
• 关键词: AIDS Dementia Complex; AIDS/HIV problem; Acquired Immunodeficiency Syndrome; Address; Adherence; Adult; Adverse effects; Affect; Africa South of the Sahara; Aftercare; Ambulatory Care; Anti-Retroviral Agents; Area; Award; Basic Science; Biomedical Research; Brain; California; Caring; Cerebrospinal Fluid; Clinical; Clinical Investigator; Clinical Research; Clinical Sciences; Clinical Trials; Cognition; Cohort Studies; Collaborations; Communicable Diseases; Control Groups; Data; Developing Countries; Diagnosis; Diagnostic; Disease; Drug Kinetics; Education; Effectiveness; Enrollment; Environment; Epidemiology; Familiarity; Family; Funding; Future; Goals; HIV; HIV-1; Health; Health Sciences; Home environment; Immunology; Impaired cognition; Impairment; Incidence; Individual; Infection; Inflammation; Institution; International; Kenya; Laboratory Research; Lead; Measures; Mentored Research Scientist Development Award; Mentors; Methods; Neopterin; Nervous system structure; Neuraxis; Neurocognitive; Neurologic; Neurological outcome; Neurologist; Neurology; Neuropsychological Tests; Neuropsychology; Neurovirology; Observational Study; Patient Care; Patients; Penetration; Performance; Pharmaceutical Preparations; Physicians; Plasma; Prevalence; Price; Province; Proxy; RNA; Randomized Controlled Trials; Regimen; Reporting; Research; Research Infrastructure; Research Personnel; Research Training; Resources; Risk; Sampling; San Francisco; Services; Site; Testing; Training; Translational Research; Treatment Effectiveness; Tropical Medicine; Universities; Viral; Work; antiretroviral therapy; base; career; clinical research site; cohort; cost effective; design; effective intervention; effective therapy; experience; follow-up; functional status; global health; implementation science; improved; innovation; mortality; multidisciplinary; neurophysiology; neuropsychological; patient oriented; programs; prospective; psychologic; repository; research study; treatment program; virology

DESCRIPTION (provided by applicant): This is an application for a K01 award for Dr. Ana-Claire Meyer, a neurologist at the University of California, San Francisco. Dr. Meyer is establishing herself as a young investigator focused on patient-oriented clinical research on infectious diseases of the nervous system in resource-limited settings. Dr. Meyer will obtain additional research training through coursework, tutorials and practical experience in the following areas: applying state-of-the-art research and laboratory methods in tropical medicine, neurophysiology, neuropsychology and neurovirology to global health settings; designing and implementing clinical trials; and additional training in implementation science and global health. With this award, she will obtain the didactic training and mentored clinical research experience she needs to establish herself as an independent researcher and successfully compete for R01 funding. This K01 award will enable Dr. Meyer to take the next steps to achieve her long-term career goal: to become a leading researcher developing, evaluating, and implementing innovative and cost-effective interventions to diagnose and treat neurologic conditions in resource limited settings such as sub-Saharan Africa. The Environment: To support her career objectives and research plan, Dr. Meyer has assembled a multidisciplinary mentoring committee comprised of senior clinical investigators who will provide added expertise in conducting clinical, epidemiological, and translational research on HIV-associated neurocognitive disorders within an international collaborative. Her primary mentor is Dr. Richard W. Price, and her co-mentors are Drs. Gretchen Birbeck and Craig Cohen. Her developing country mentor will be Dr. Elizabeth Bukusi. Her home institution, the University of California San Francisco (UCSF), is considered one of the nation's premier health sciences, training, and research centers and has a well-established reputation in biomedical research. The Department of Neurology is a leading academic center dedicated to excellence in patient care, education and research. The HIV Neurology Research Program conducts clinical and basic science research on the effects of HIV on the nervous system and includes active collaborations with clinical HIV, virology and immunology programs. Her international collaborative site, Family AIDS Care and Education Services (FACES), is an HIV/AIDS care and treatment program based in Kenya. FACES currently provides HIV care in 83 facilities in Nyanza Province and Nairobi. As of December 31, 2010, FACES had 96,821 patients cumulatively enrolled with 37,310 patients on ART. FACES clinical sites have previous experience with research studies. In addition, FACES sites are staffed by well-trained clinicians and ancillary staff and have the necessary infrastructure and oversight to complete this study. Research Plan: We estimate that HIV-associated neurocognitive disorders (HAND) may affect nearly 188,000 individuals in Nyanza Province, Kenya, 5.5 million across sub-Saharan Africa, and 8.25 million worldwide. HAND has been associated with poor adherence to antiretroviral therapy (ART) and with higher mortality. Combination ART is the most effective treatment for HAND to date and some studies have suggested that ART with higher penetration into the central nervous system (CNS) lead to improved neurologic outcomes. However, these studies have important limitations and thus there is insufficient evidence to recommend ART with high CNS penetration effectiveness (CPE) for the treatment of HAND. The objective of this application is to determine whether it is important to treat HIV-infected individuals with neurocognitive disorders with ART with high CPE. Because of limited ART choices in Kenya, we will be able to directly compare the effects of specific ART regimens thus avoiding the limitations of prior studies. The central hypothesis is that, among individuals with HAND, ART with high CPE lead to improved neurologic outcomes as compared to ART with low CPE. We will enroll a prospective observational cohort of 200 HIV-infected ART- naove adults with HIV-associated cognitive impairment. Aim 1: To determine the effect of common ART regimens with different CNS pharmacokinetics on the neuro-psychological performance of ART-naove HIV infected adults with cognitive impairment in western Kenya Over a follow-up period of 48 weeks, we will determine the effect of four ART regimens on three NP measures: a composite score, the QNPZ-4, and level of impairment using common diagnostic criteria. Aim 2: To determine the effect of common ART regimens with different CNS pharmacokinetics on viral replication and inflammation in the cerebrospinal fluid (CSF) of ART-naove HIV infected adults with cognitive impairment in western Kenya In a sub-sample of 100 individuals, we will determine the effect of ART regimens on: (1) CSF HIV-1 RNA; (2) CSF:plasma HIV-1 RNA ratio; (3) CSF WBC count; (4) CSF neopterin. We will also create a unique repository of samples for future collaborative studies. Aim 3: To determine whether there is a practice effect on the neuropsychological test battery We will re-administer our NP battery to 100 HIV un-infected individuals who we have previously studied. These specific aims logically build toward an R01 to determine the effect of ART on combined systemic and neurologic outcomes in cognitively impaired individuals in a randomized controlled trial. PUBLIC HEALTH RELEVANCE: A better understanding of which antiretroviral therapies lead to the greatest improvements in cognition among individuals with HIV-associated neurocognitive disorders could help physicians better tailor antiretroviral therapy. Ultimately, this could lead to improved cognition, functional status and health for individuals with HIV-associated neurocognitive disorders.

描述（由申请人提供）：这是加利福尼亚大学旧金山分校的神经科医生Ana-Claire Meyer博士的K01奖。 Meyer博士正在建立自己的年轻研究者，该研究人员专注于以患者为导向的临床研究，该研究对资源有限的环境中神经系统的传染病。 Meyer博士将通过课程，教程和实践经验在以下领域获得其他研究培训：在热带医学，神经生理学，神经心理学和神经病毒学中，将最先进的研究和实验室方法应用于全球健康环境；设计和实施临床试验；以及实施科学和全球健康方面的其他培训。有了这个奖项，她将获得教学培训，并为自己建立独立研究人员而需要的临床研究经验，并成功地争夺R01资金。这项K01奖将使迈耶博士能够采取下一步的步骤来实现她的长期职业目标：成为一名领先的研究人员，开发，评估和实施创新且具有成本效益的干预措施，以诊断和治疗在诸如撒哈拉以南非洲以外的限制设置中的神经系统状况。 环境：为了支持她的职业目标和研究计划，迈耶博士组建了一个由高级临床研究人员组成的跨学科指导委员会，这些委员会将在国际协作中提供有关HIV相关神经认知障碍的临床，流行病学和转化研究的更多专业知识。她的主要导师是理查德·W·普莱斯（Richard W. Price）博士，她的联合委托人是博士。格蕾琴·比贝克（Gretchen Birbeck）和克雷格·科恩（Craig Cohen）。她的发展中国家导师将是伊丽莎白·布库西（Elizabeth Bukusi）博士。 她的家庭机构，加利福尼亚大学旧金山分校（UCSF），被认为是美国首要的健康科学，培训和研究中心之一，在生物医学研究中享有良好的声誉。神经病学系是一个领先的学术中心，致力于卓越的患者护理，教育和研究。 HIV神经病学研究计划对HIV对神经系统的影响进行临床和基础科学研究，并包括与临床HIV，病毒学和免疫学计划的积极合作。她的国际合作网站，家庭艾滋病护理和教育服务（FACES）是肯尼亚的艾滋病毒/艾滋病护理和治疗计划。面孔目前在Nyanza省和内罗毕的83个设施中提供艾滋病毒护理。截至2010年12月31日，面孔有96,821名患者累计招募了37,310名ART患者。面孔临床站点以前在研究方面具有经验。此外，面孔站点由训练有素的临床医生和辅助人员组成，并具有必要的基础设施和监督以完成这项研究。 研究计划：我们估计，与艾滋病毒相关的神经认知障碍（手）可能会影响肯尼亚Nyanza省的近188,000名个人，撒哈拉以南非洲的550万人，全球825万。手与对抗逆转录病毒疗法（ART）的依从性不佳以及较高的死亡率有关。联合艺术是迄今为止手工治疗的最有效治疗方法，一些研究表明，对中枢神经系统（CNS）的渗透率更高会导致神经系统结局的改善。但是，这些研究具有重要的局限性，因此没有足够的证据来推荐具有高CNS渗透有效性（CPE）的ART来治疗手。该应用的目的是确定治疗患有高CPE ART神经认知疾病的HIV感染者是否重要。由于肯尼亚的艺术选择有限，我们将能够直接比较特定艺术方案的影响，从而避免先前研究的局限性。中心假设是，与低CPE的ART相比，在具有高CPE的手术的个体中，具有高CPE的ART导致神经系统结局的改善。我们将招募200名受HIV相关认知障碍的200名HIV感染艺术成年人的前瞻性观察队列。 目的1：确定具有不同CNS药代动力学的常见艺术方案对肯尼亚西部的Art-Naove HIV感染成年人在48周内具有认知障碍的成年人的神经心理表现的影响，我们将确定四种NP测度的四个ART方案对QNPZ-4和CRETIA的效果：使用QNPZ-4和Impair commia Impair and Immabia。 目的2：确定具有不同CNS药代动力学的常见艺术方案对100个个体的肯尼亚州西亚的认知障碍的成年人的脑脊液（CSF）对100个个体的认知障碍的成年人的脑脊液（CSF）的病毒复制和炎症的影响，我们将确定艺术方案对：（1）CSF HIV-1 rna的影响： （2）CSF：血浆HIV-1 RNA比率； （3）CSF WBC计数； （4）CSF Neopterin。我们还将为未来的协作研究创建一个独特的样本存储库。 AIM 3：为了确定是否对神经心理测试电池有练习效应，我们将重新将NP电池重新管理到我们以前研究过的100个未感染的HIV未感染的人。这些特定的目的从逻辑上建立在R01上，以确定在随机对照试验中，在认知受损的个体中，艺术对系统和神经系统结合的影响。 公共卫生相关性：更好地理解哪种抗逆转录病毒疗法会导致患有HIV相关神经认知疾病的个体认知能力的最大改善，这可以帮助医生更好地量身定制抗逆转录病毒疗法。最终，这可能会导致患有艾滋病毒相关神经认知疾病的人的认知，功能状况和健康。